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Rachana Patel, Janis Fleming, Ernest Mui, Carolyn Loveridge, Peter Repiscak, Arnaud Blomme, Victoria Harle, Mark Salji, Imran Ahmad, Katy Teo, Freddie C Hamdy, Ann Hedley, Niels van den Broek, Gillian Mackay, Joanne Edwards, Owen J Sansom, Hing Y Leung
Metastatic castration-resistant prostate cancer (mCRPC) is a lethal form of treatment-resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre-clinical human and murine mCRPC models, we show that SPRY2 deficiency leads to an androgen self-sufficient form of CRPC Mechanistically, HER2-IL6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD3B1 and increases SRB1-mediated cholesterol uptake in SPRY2-deficient tumours...
March 14, 2018: EMBO Molecular Medicine
Caixia Guo, Ru Ma, Xiaoying Liu, Tian Chen, Yang Li, Yang Yu, Junchao Duan, Xianqing Zhou, Yanbo Li, Zhiwei Sun
Oxidized low-density lipoprotein (oxLDL), a marker of hyperlipidemia, plays a pivotal role in the development of atherosclerosis through the induction of macrophage-derived foam cell formation and thereafter apoptosis. Previous studies have indicated that silica nanoparticle (SiNPs) may exert a proatherogenic role, which could induce endothelial dysfunction, and monocytes infiltration. However, little is known about SiNPs' effects on macrophage-derived foam cell formation and apoptosis in the pathogenesis of atherosclerosis...
March 10, 2018: Science of the Total Environment
Laiqiang Gao, Haiying Wang, Xuehong Wang, Ailan Li, Qiang Ma
Candida albicans, a human fungal pathogen, is able to tolerate certain levels of environmental stresses. Its cell wall plays an important role in cellular homeostasis, responding to environmental stimuli. SRB1 gene encodes a GDP-mannose pyrophosphorylase that catalyzes the formation of the major cell wall component, mannan. The exact relationship between SRB1 and various stresses is not yet fully understood. In current study, C. albicans SC5314 cells were exposed to oxidative, hyperosmotic, and thermal stresses...
February 14, 2018: Medical Mycology: Official Publication of the International Society for Human and Animal Mycology
Yuzhi Wu, Jian-Wen Qiu, Pei-Yuan Qian, Yong Wang
In deep-sea cold seeps, microbial communities are shaped by geochemical components in seepage solutions. In the present study, we report the composition of microbial communities and potential metabolic activities in the surface sediment of Jiaolong cold seep at the northern South China Sea. Pyrosequencing of 16S rRNA gene amplicons revealed that a majority of the microbial inhabitants of the surface layers (0-6 cm) were sulfur oxidizer bacteria Sulfurimonas and archaeal methane consumer ANME-1, while sulfate reducer bacteria SEEP-SRB1, ANME-1 and ANME-2 dominated the bottom layers (8-14 cm)...
February 13, 2018: Extremophiles: Life Under Extreme Conditions
Yvonne Baumer, Qimin Ng, Gregory E Sanda, Amit K Dey, Heather L Teague, Alexander V Sorokin, Pradeep K Dagur, Joanna I Silverman, Charlotte L Harrington, Justin A Rodante, Shawn M Rose, Nevin J Varghese, Agastya D Belur, Aditya Goyal, Joel M Gelfand, Danielle A Springer, Christopher Ke Bleck, Crystal L Thomas, Zu-Xi Yu, Mårten Cg Winge, Howard S Kruth, M Peter Marinkovich, Aditya A Joshi, Martin P Playford, Nehal N Mehta
Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation...
January 11, 2018: JCI Insight
Rui Kuai, Chitra Subramanian, Peter T White, Barbara N Timmermann, James J Moon, Mark S Cohen, Anna Schwendeman
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and has a 5-year survival rate of <35%. ACC cells require cholesterol for steroid hormone production, and this requirement is met via expression on the cell surface of a high level of SRB1, responsible for the uptake of high-density lipoproteins (HDLs), which carry and transport cholesterol in vivo. Here, we describe how this natural lipid carrier function of SRB1 can be utilized to improve the tumor-targeted delivery of a novel natural product derivative - withalongolide A 4,19,27-triacetate (WGA-TA) - which has shown potent antitumor efficacy, but poor aqueous solubility...
2017: International Journal of Nanomedicine
Connor T Skennerton, Karuna Chourey, Ramsunder Iyer, Robert L Hettich, Gene W Tyson, Victoria J Orphan
The anaerobic oxidation of methane by anaerobic methanotrophic (ANME) archaea in syntrophic partnership with deltaproteobacterial sulfate-reducing bacteria (SRB) is the primary mechanism for methane removal in ocean sediments. The mechanism of their syntrophy has been the subject of much research as traditional intermediate compounds, such as hydrogen and formate, failed to decouple the partners. Recent findings have indicated the potential for extracellular electron transfer from ANME archaea to SRB, though it is unclear how extracellular electrons are integrated into the metabolism of the SRB partner...
August 1, 2017: MBio
Anne-Marie Saillenfait, Jean-Philippe Sabaté, Flavien Denis, Guillaume Antoine, Alain Robert, Alain-Claude Roudot, Dieynaba Ndiaye, Ethel Eljarrat
Pregnant Sprague-Dawley rats were administered the insecticide α-cypermethrin at doses of 0.1, 1, 5, or 10mg/kg/day, or di-isobutyl phthalate (DIBP) at 250mg/kg/day, by gavage, from gestation day (GD) 13 to 19. Testicular testosterone production and the expression of several key genes related to cholesterol and androgen synthesis and transport were assessed in GD 19 male fetuses. Dams treated with 10mg/kg/day of α-cypermethrin showed clinical signs of neurotoxicity and reduced body weight gain. α-Cypermethrin had no significant effect on post-implantation loss, fetal weight, incidence of male fetuses per litter, or anogenital distance of the male fetuses...
June 24, 2017: Reproductive Toxicology
Clara V Perani, Dominik Langgartner, Nicole Uschold-Schmidt, Andrea M Füchsl, Inga D Neumann, Stefan O Reber, David A Slattery
Increased basal glucocorticoid secretion and a reduced glucocorticoid response during acute stress, despite only minor changes in the secretion of the major secretagogue adrenocorticotropic hormone (ACTH), have been documented in the peripartum period in several species. We recently showed that the adrenal gland, the site of glucocorticoid synthesis, undergoes substantial postpartum-associated plasticity in the rat at mid-lactation. Here, we asked the question whether adrenal changes already take place around parturition in the rat and in another species, namely the mouse...
May 19, 2017: Stress: the International Journal on the Biology of Stress
Hiten D Mistry, Lesia O Kurlak, Yosef T Mansour, Line Zurkinden, Markus G Mohaupt, Geneviève Escher
Preeclampsia is a pregnancy-specific condition that leads to increased cardiovascular risk in later life. A decrease in cholesterol efflux capacity is linked to CVD. We hypothesized that in preeclampsia there would be a disruption of maternal/fetal plasma to efflux cholesterol, as well as differences in the concentrations of both placental sterol 27-hydroxylase (CYP27A1) and apoA1 binding protein (AIBP). Total, HDL-, and ABCA1-mediated cholesterol effluxes were performed with maternal and fetal plasma from women with preeclampsia and normotensive controls (both n = 17)...
June 2017: Journal of Lipid Research
S Sini, D Deepa, S Harikrishnan, N Jayakumari
Although high-density lipoprotein is atheroprotective, it can become dysfunctional in chronic inflammatory conditions and increase cardiovascular risk. We previously demonstrated that HDL from subjects with documented coronary artery disease is dysfunctional and is pro-oxidant/proinflammatory in macrophages. Here we examined the influence of dysfunctional/proinflammatory HDL (piHDL) on lipid accumulation in human macrophages, in comparison to functional HDL (nHDL). Exposure of macrophages to piHDL, in contrast to nHDL, resulted in oxidative stress and marked uptake of lipids from piHDL, leading to the formation of foam cell phenotype as noted by oil red O staining with concomitant increase in total cellular cholesterol content...
March 2017: Molecular and Cellular Biochemistry
Ilaria Crivellari, Claudia Sticozzi, Giuseppe Belmonte, Ximena M Muresan, Franco Cervellati, Alessandra Pecorelli, Carlotta Cavicchio, Emanuela Maioli, Christos C Zouboulis, Mascia Benedusi, Carlo Cervellati, Giuseppe Valacchi
For its critical location, the skin represents the major interface between the body and the environment, therefore is one of the major biological barriers against the outdoor environmental stressors. Among the several oxidative environmental stressors, cigarette smoke (CS) has been associated with the development and worsening of many skin pathologies such as acne, dermatitis, delayed wound healing, aging and skin cancer. In our previous work we have demonstrated that CS is able to affect genes involved in skin cholesterol trafficking, among which SRB1, a receptor involved in the uptake of cholesterol from HDL, seems to be very susceptible to the oxidative stress induced by CS...
January 2017: Free Radical Biology & Medicine
Takuya Kikuchi, Kana Orihara, Fusaka Oikawa, Song-Iee Han, Motoko Kuba, Kanako Okuda, Aoi Satoh, Yoshinori Osaki, Yoshinori Takeuchi, Yuichi Aita, Takashi Matsuzaka, Hitoshi Iwasaki, Shigeru Yatoh, Motohiro Sekiya, Naoya Yahagi, Hiroaki Suzuki, Hirohito Sone, Yoshimi Nakagawa, Nobuhiro Yamada, Hitoshi Shimano
OBJECTIVE: The transcription factor cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) is highly expressed in the liver and small intestine. Hepatic CREBH contributes to glucose and triglyceride metabolism by regulating fibroblast growth factor 21 (Fgf21) expression. However, the intestinal CREBH function remains unknown. METHODS: To investigate the influence of intestinal CREBH on cholesterol metabolism, we compared plasma, bile, fecal, and tissue cholesterol levels between wild-type (WT) mice and mice overexpressing active human CREBH mainly in the small intestine (CREBH Tg mice) under different dietary conditions...
November 2016: Molecular Metabolism
Line S Bisgaard, Christina K Mogensen, Alexander Rosendahl, Helena Cucak, Lars Bo Nielsen, Salka E Rasmussen, Tanja X Pedersen
Macrophages are heterogeneous and can polarize into specific subsets, e.g. pro-inflammatory M1-like and re-modelling M2-like macrophages. To determine if peritoneal macrophages (PEMs) or bone marrow derived macrophages (BMDMs) resembled aortic macrophages from ApoE-/- mice, their M1/M2 phenotype, inflammatory status, and lipid metabolism signatures were compared. oxLDL accumulation was similar in PEMs and BMDMs. On protein expression level, BMDMs showed an M2-like CD206(high)CD11c(low) profile, while cholesterol loading led to enhanced CD11c expression and reduced MCP-1 secretion...
October 13, 2016: Scientific Reports
Juwen C DuBois, A George Smulian
The Histoplasma capsulatum sterol regulatory element binding protein (SREBP), Srb1 is a member of the basic helix-loop-helix (bHLH), leucine zipper DNA binding protein family of transcription factors that possess a unique tyrosine (Y) residue instead of an arginine (R) residue in the bHLH region. We have determined that Srb1 message levels increase in a time dependent manner during growth under oxygen deprivation (hypoxia). To further understand the role of Srb1 during infection and hypoxia, we silenced the gene encoding Srb1 using RNA interference (RNAi); characterized the resulting phenotype, determined its response to hypoxia, and its ability to cause disease within an infected host...
2016: PloS One
Sara E Thomas, Earl H Harrison
The xanthophylls, lutein and zeaxanthin, are dietary carotenoids that selectively accumulate in the macula of the eye providing protection against age-related macular degeneration. To reach the macula, carotenoids cross the retinal pigment epithelium (RPE). Xanthophylls and β-carotene mostly associate with HDL and LDL, respectively. HDL binds to cells via a scavenger receptor class B1 (SR-B1)-dependent mechanism, while LDL binds via the LDL receptor. Using an in-vitro, human RPE cell model (ARPE-19), we studied the mechanisms of carotenoid uptake into the RPE by evaluating kinetics of cell uptake when delivered in serum or isolated LDL or HDL...
October 2016: Journal of Lipid Research
Ying Zhang, Bin Liao, Miaoling Li, Min Cheng, Yong Fu, Qing Liu, Qi Chen, Hongduan Liu, Yibing Fang, Gen Zhang, Fengxu Yu
AIM: The aim of this study was to explore whether transmembrane flow shear stress could regulate eNOS expression and mediate endothelial cell function via SR-B1 signaling transduction. METHODS: Parallel-plate flow chamber was used to impose laminar shear stress and evaluate the effect of shear stress upon human umbilical vein endothelial cells (HUVECs). The expression of SR-B1 and eNOS at both RNA and protein levels was detected under different dynamic conditions...
October 2016: Cardiovascular Therapeutics
R Gardinal, G D Calomeni, N R B Cônsolo, C S Takiya, J E Freitas, J R Gandra, T H A Vendramini, H N Souza, F P Rennó
OBJECTIVE: Two experiments were performed to evaluate the effects of coated slow-release urea on nutrient digestion, ruminal fermentation, nitrogen utilization, blood glucose and urea concentration (Exp 1), and average daily gain (ADG; Exp 2) of steers. METHODS: Exp 1: Eight ruminally fistulated steers [503±28.5 kg body weight (BW)] were distributed into a d 4×4 Latin square design and assigned to treatments: control (CON), feed grade urea (U2), polymer-coated slow-release urea A (SRA2), and polymer-coated slow-release urea B (SRB2)...
January 2017: Asian-Australasian Journal of Animal Sciences
Steven Jones, Annie Boisvert, Andrada Naghi, Françoise Hullin-Matsuda, Peter Greimel, Toshihide Kobayashi, Vassilios Papadopoulos, Martine Culty
Previous work in our laboratory demonstrated that in-utero exposure to a mixture of the phytoestrogen Genistein (GEN), and plasticizer DEHP, induces short- and long-term alterations in testicular gene and protein expression different from individual exposures. These studies identified fetal and adult Leydig cells as sensitive targets for low dose endocrine disruptor (ED) mixtures. To further investigate the direct effects and mechanisms of toxicity of GEN and DEHP, MA-10 mouse tumor Leydig cells were exposed in-vitro to varying concentrations of GEN and MEHP, the principal bioactive metabolite of DEHP...
April 29, 2016: Toxicology
Mei Ha, Xie Guan, Li Wei, Peng Li, Min Yang, Changjiang Liu
Di-(2-ethylhexyl) phthalate (DEHP) has reproductive toxicity and can affect male reproductive development. In order to clarify adverse effects of DEHP on testicular physiology and testosterone production, Sprague-Dawley (SD) rats were dosed daily with DEHP by gavage for 30days; TM3 cells (mouse Leydig cell line) were treated with DEHP for 24h after pretreatment with vitamin C or U0126. Results indicated that the hypothalamic-pituitary-testis (HPT) axis was disturbed and serum testosterone, LH and FSH levels were decreased following DEHP exposure...
September 1, 2016: Science of the Total Environment
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